United States Patent 0 i ice
1
2
The following examples illustrate in greater particular
2,909,523
' ity the preparation of representative compounds of the
SUBSTITUTED PIPERAZINES
‘
N
‘2,909,523
Patented Oct. 20, 1959,
present invention.
METHOD'OF .
PREPARING THE SAME
,
’
5
Frederick. L. “Bach, Jr., and Herbert J. 'Brabander, Pearl’
Example 1
A. suspension consisting of 26.6 grams'of l,2,3,4-tetra
' River, and» Samuel Kushner, Nanuet, N.Y., assignors
' hydroquinoline, 24.9 grams of 2-bromoethanol, 16.8
».to'-American Cyanamid Company, New York, N.Y., a
corporation of Maine
grams of sodium bicarbonate, and 150 ml. of ethanol was
re?uxed 15 hours. After this period of time, the ethanol
'Was removed by distillation under reduced pressure at
'water bath temperature. The brown, oily residue was
N0 Drawing. Application October ‘11, 1957 . .
'Serial 'No. 689,468
r
‘
'basi?ed with cold, aqueous, concentrated potassium hy
_8 Claims. (Cl. 260-468)
droXide solution and then extracted with chloroform. The
chloroform extracts were combined, decolorized with ac
This invention relates to new organic compounds.
More particularly, it relates to 1-[omega-(4-substituted-1
piperazinyllalkyl] benzoheterocyclic compounds, wherein.
thehetero atom is nitrogen, and methods of preparing
tivated charcoal, fractionated, and the product, l-(beta
hydroxyethyl)-1,2,3,4-tetrahydroquinoline, was collected
at 193° .C., 28 to 29‘ mm. pressure.
Seventeengramsof l-(beta-hydroxyethyl) -1,2,3,4-tetra
hydroquinoline and 200 ml. of 48% hydrobromic acid
"l’hepreparation of ring-saturated ,quinoline compounds 20 Were.combined with cooling in a distilling vessel and. sub
the same.
>
'
I
is known; for example, 1.-‘(S-aminoamyldecahydroquino
line,..(¢Ber., 59B, 1786-91 [1926])). These compounds,
_ jected toa slow distillation atatmospheric pressure. After
however, do not possess effective blood pressure depressor
distillation was discontinued and the reaction mixture was
collecting approximately 175ml. of hydrobromicacid, the
or adrenergic blocking effect, which is true .of‘the com
re?uxed‘ for 15hours. Thedark-brown, aqueous solution
pounds ‘of the present invention.
26 was then. concentrated under reduced pressure at 70° .‘C.
The present compounds may be illustrated by the fol
. to a-viscousyresidue,.which solidi?ed on standing in an
lowing general formula:
CH2)":
' evacuateddesiccaton. Sixteen grams of the crude l-(beta
bromoethyl) -1,2,3,4 - tetrahydroquinoline monohydrobro
mide obtainedin this manner was condensed with an
30 excess of l-phenylpiperazine toyield a semi-crystalline
reaction mass, which was heated at 95° C. for 24 hours.
'1 'IIhe-react-ion-mass was triturated with two 100~m1. por-
tions of water, ?ltered, and the water-insoluble material
in rwhich‘tR is an- aryl, aralkyl, pyridyl, or carbloweralkoxy
recrystallized twice ‘from a benzene-ether vsolution. The
radical, R’ is hydrogen or a lower alkyl radical, m‘is 35 desired 1-:[‘2-(4-phenyl-1-piperazinyl)ethyl]-1,2,3,4-tetra
an integer from 2 to 4, and n1 is an integer from 1 to 10.
' hydroquinoline melted at‘ 110° C. to 112° C.
The compounds of the present invention possess amino.
Example 2
groups and, therefore, will form acid addition salts.
Three-and-one-half
grams
of 1-[2-( 4aphenyl-l-piper
. The present compounds are, in general, crystalline
solids. They are soluble in the usual organic solvents, 40 azpinyl) ethyl] -1,2,3,4-tetrahydroquinoline was treated with
, one molar equivalent of 3.11 N‘hydrochloric acid, and
such addition
acid
as benzene,
saltschloroform,
are solubletoluene,
in Water.and the like.
the resulting salt was recrystallized from ethanol. A pure
sample of the monohydrochloride of 1-[2-(4-phenyl-1
The compounds of the present invention can be prepared
piperazinyDethyl]-1,2,3,4-tetrahydroquinoline melted at
by several methods. ~ The preferred method is to heat at
23519., to 240-" v0.
re?uxing temperature in an alcoholic solvent a bicyclic
Example _3
benzoheterocyclic compound containing one nitrogen atom
with an omega haloalkanol; The condensation-‘product is
The monohydrobromide'of 1-(beta-bromoethyl)-l,2,3,
heated with hydrobrornic acid, and the resulting. l-(omega
4-tetrahydroquinoline (16.0 grams) was condensed with
haloalkyl)benzoheterocyclic derivative is ?nally reacted.
24.6 grams of I-(Z-pyridyDpiperazine in‘the absence of
with a. l-substituted piperazine to produce the desired 50 a solvent. ,After standing one hour, the semi-solid reac
compounds. The latter reaction is carried out .at a-tem
perat-ure of from 5.0” to 125° C. with or without a solvent.
tion’mass was heated 18 hours at 95° C. and then cooled
to room temperature. The’ gummy product was treated
The present compounds can also be prepared by heat
with 100ml. of water, made strongly alkaline with potas
ing a 4-substituted-l-(omega-haloalkylene)piperazine hy
sium hydroxide solution (50%), and extracted with
drohalide. with the bicyclic. benzoheterocyclic .compound. 55 chloroform. After decolorizing'the combined extracts,
The product can then be recovered by treating the reac
tionmass with a strong base, extracting with an organic
solvent, and,v following removal of the solvent, further
purifying the product by fractional distillation.
the solvent‘ was removed, and the oily residuewas dis
tilled under reduced pressure. A forerun boiling at 140°
C.'>to:'160° 'C. at 0.6 mm. pressure was-discarded and 1
{2-[4-(2'-pyridyl)-1-piperazinyl]ethyl}-1,2,3,4 - tetrahy
60
The compounds of the present invention are orally
droquinoline was collected at 185°—195° C. at 0.7 mm.
active hypotensive agents, which have the ability to lower
pressure.
blood pressure for a long period of time. In general, the
intensity and ‘duration of blood pressure depressor effect
Example 4
A mixture consisting of 23.1 grams of l-(beta-bromo
is comparable to the commonly used hydralazine hydro
chloride or hexamethonium chloride. The compounds 65 ethyl)-4-phenylpiperazine hydrobromide and 23.8 grams
of indoline was heated at water bath temperature for 15 of the present invention are also active as adrenergic and
hours. The quasi-crystalline reaction mass was cooled,
ganglionic blockading agents of long duration.
made strongly alkaline with an excess of concentrated
They can be administered-in the usual pharmaceutical
aqueous sodium hydroxide solution and subjected to a
forms, such as tablets, capsules, pills, etc., or they can be
administered as constituents of bulk powders or individual 70 steam distillation. Two 100-m1. portions of ether were
used to extract the undistilled organic material, and the
dosage powders or liquids.
2,909,523
3
4
ether extracts were combined, decolorized with charcoal,
and dried over anhydrous potassium carbonate. After
removing the solvent at reduced pressure, the oily residue
was distilled, and l-[2-(4-phenyl-1-piperazinyl)ethyllin
then added to a suspension of 10.6 g. of l-benzylpiper
azine and 5.7 g. of sodium bicarbonate in 200 ml. of eth
anol. The mixture is re?uxed ‘for ?fteen hours, ?ltered,
doline was collected at 265° C. to 270° C., 0.2 mm.
pressure. The distillate solidi?ed on standing and melted
at 58° C.—60° C.
centrated, aqueous sodium hydroxide solution is added to
the residue and two 100 ml. portions of chloroform are
and concentrated to a yellow oil.
An excess of con
used- to extract the organic material.
Example 5
>
The combined chloroformic extracts are decolorize
using activated charcoal, dried over anhydrous potassium
l-[2-(4-phenyl - 1 - piperazinyl)ethyl]indoline (1.12
grams) was partially dissolved in 20 ml. of ethanol and 10 carbonate, ?ltered, and then concentrated to a viscous oil,
treated with 0.95 ml. of 3.8090 N hydrochloric acid. The
solution was warmed, decolorized with activated charcoal,
and concentrated to 10 ml. On cooling, ether was added
until turbidity developed, and on standing the monohy 15
which solidi?ed on standing.
Approximately 15.3 g.
(70%) of 1-[a-(4-benzyl-1-piperazinyl)butyryllindoline
is obtained in this manner; melting point 113 °—l15° C.
Using a Soxhlet extractor, 13.1 g. of 1-[a-(4-benzyl-1
piperazinyl)butyryl]indoline is gradually dissolved in a
drochloride of 1~[2-(4-phenyl - 1 - piperazinyl)ethyl]in
slurry of lithium aluminum hydride (4.2 g.) in 175 ml. of
doline was deposited as needle crystals; melting point 202°
anhydrous ether. After addition is complete, the suspen
C. to 205° C. with decomposition.
sion is re?uxed gently for 24 hours and then decomposed,
Example 6
using water and 15% sodium hydroxide solution. The
20 ethereal‘ layer is separated, dried over anhydrous copper
Indoline (2.8 grams)jwas mixed with 5.3 grams of 1
sulfate, and concentrated to a yellow, oily residue. The
omega-bromodecyl-4-carbethoxypiperazine hydrobromide,
crude reaction product is then fractionated under reduced
and the resulting mixture was heated at steam bath tem
prespsure'to yield 6.0 g. of 1-[2-(4-benzyl-l-piperazinyl)
perature for two hours. Water was then added to the
reaction mass, which was made basic using a concentrated, 25 butyllindoline; boiling point 240°-245° C. (5.0 mm.).
Reduction of the carbonyl group was veri?ed by an in
aqueous potassium hydroxide and extracted with chloro
frared analysis.
form. The combined chloroform extracts (100 ml.) were
We claim:
decolorized with activated charcoal and concentrated to
a heavy, brown oil. The desired product, 1-[10-(4-car
bethoxy-l-piperazinyl)decyllindoline (boiling point 230°
30
1. A compound selected from the group having the
general formula:
C.—235° C. at 0.15 mm. pressure) was obtained by frac
tionally distilling the oily residue.
Example 7
Ten grams of l-(beta-hydroxyethyl)-4-phenylpiper 35
azine was treated with 200 ml. of 48% hydrobromic acid
at 0°—5° C. and the resulting mixture was subjected to a
slow distillation at atmospheric pressure. After 155 ml.
, in which R is a member of the group‘ consisting of phenyl,
of hydrobromic acid had been collected, the residual ma
benzyl,,pyridyl, and carbloweralkoxy radicals, R’ is a
terial was re?uxed for ten hours and then concentrated 40 member of the group consisting of hydrogen and lower
under reduced pressure to a semi-crystalline mass. This
alkyl radicals, in is an integer from 2 to 4, ru is an integer
crude material solidi?ed on standing two days in an evacu
from 1 to 10, and acid addition salts thereof.
ated desiccator. The 1-(beta-bromoethyl)-4-phenylpiper
azine hydrobromide (4.5 g.) was condensed with 1,2,3,4
2. A l-[omega-(4-phenyl-1-piperazinyl)alkyl] -1,2,3,4
tetrahydroquinoline wherein the alkyl radical contains 1
tetrahydroquinoline, which was added in a four-fold ex
to 10 carbon atoms.
I 3. The compound 1-[2-(4-phenyl-1-piperazinyl)ethyl]
cess, and the quasi-crystalline reaction product was Washed
with two 100Frnl. portions of water. The insoluble prod
uct was recrystallized from benzene to yieldl-[2-(4-phen
l,2,3,4'-tetrahydroquinoline.
ylpiperazinyl) ethyl] -1,2,3,4-tetrahydroquinoline, melting
point 110“ C. to 112° C.
50
Example 8
An ethereal solution of a-bromobutyryl chloride (18.6
g. in 100 ml. of anhydrous ether) is added with stirring
to a cooled, ethereal solution of 23.8 g. of indoline in 55
300 ml. of anhydrous ether. An immediate reaction
takes place, and after the last addition of acid chloride,
the precipitated indoline monohydrochloride is removed
‘by ?ltration. The clear ?ltrate is concentrated and on
cooling deposits approximately 16.0 g. of lu-bromobutyryl 60
indoline.
Sixteen grams of crude loc-bromobutyryl indoline are
‘
.
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4. The compound 1-[2-(4-phenyl-1-piperazinyl)ethyl]-v
1,2,3,4-tetrahydroquinoline hydrochloride.
5. The compound 1-{2-[4-(2’-pyridyl)-1-piperazinyl]
ethyl}-1,2,3,4-tetrahydroquinoline.
6. The compound 1-[2-(4-phenyl-1-piperazinyl)ethyl]
indoline.
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7. The compound 1-[10-(4-carbethoxy-l-piperazinyl)
decyllindoline.
.
8. The compound 1-[2-(4-carbethoxy-l-piperazinyl)-v
propyllindoline.
References Cited in the ?le of this patent
UNITED STATES PATENTS‘
2,786,845
Mauss et al ___________ .._ Mar. 26, 1957